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Carisbamate (RWJ-333369) inhibits glutamate transmission in the granule cell of the dentate gyrus.
Neuropharmacology 2011; 61(8):1239-47N

Abstract

Carisbamate (CRS, RWJ-333369) is a novel antiepileptic drug awaiting approval for use in the treatment of partial and generalized seizures. Our aim was to determine whether CRS modulates synaptic transmission in the dentate gyrus (DG) and the underlying mechanism. The whole-cell patch-clamp method was used to record AMPA receptor- and NMDA receptor-mediated excitatory postsynaptic currents (EPSC(AMPA) and EPSC(NMDA)) and GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) in granule cells of the DG in brain slices prepared from 3- to 5-week-old male Wistar rats. CRS (30-300 μM) inhibited the evoked EPSC(AMPA) and EPSC(NMDA) by the same extent (20%) with significantly altered CV(-2), suggesting presynaptic modulation. It did not significantly change the inward currents induced by AMPA application. The inhibitory effect of CRS on the evoked EPSC(AMPA) was not occluded by selective voltage-gated Ca(2+) channel blockers, ruling out the involvement of presynaptic Ca(2+) channels. The frequency, but not the amplitude, of spontaneous EPSC(AMPA) was significantly reduced by CRS. However, CRS did not alter either the frequency or the amplitude of TTX-insensitive miniature EPSC(AMPA), indicating an action potential-dependent mechanism was involved. In addition, CRS (100 or 300 μM) did not significantly change the amplitude of the evoked IPSCs. To summarize, our results suggest that CRS reduces glutamatergic transmission by an action potential-dependent presynaptic mechanism and consequently inhibits excitatory synaptic strength in the DG without affecting GABAergic transmission. This effect may contribute to the antiepileptic action observed clinically at therapeutic concentrations of CRS.

Authors+Show Affiliations

Department of Pharmacology, College of Medicine, National Taiwan University, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

21824485

Citation

Lee, Chun-Yao, et al. "Carisbamate (RWJ-333369) Inhibits Glutamate Transmission in the Granule Cell of the Dentate Gyrus." Neuropharmacology, vol. 61, no. 8, 2011, pp. 1239-47.
Lee CY, Lee ML, Shih CC, et al. Carisbamate (RWJ-333369) inhibits glutamate transmission in the granule cell of the dentate gyrus. Neuropharmacology. 2011;61(8):1239-47.
Lee, C. Y., Lee, M. L., Shih, C. C., & Liou, H. H. (2011). Carisbamate (RWJ-333369) inhibits glutamate transmission in the granule cell of the dentate gyrus. Neuropharmacology, 61(8), pp. 1239-47. doi:10.1016/j.neuropharm.2011.07.022.
Lee CY, et al. Carisbamate (RWJ-333369) Inhibits Glutamate Transmission in the Granule Cell of the Dentate Gyrus. Neuropharmacology. 2011;61(8):1239-47. PubMed PMID: 21824485.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carisbamate (RWJ-333369) inhibits glutamate transmission in the granule cell of the dentate gyrus. AU - Lee,Chun-Yao, AU - Lee,Meng-Larn, AU - Shih,Chien-Cheng, AU - Liou,Horng-Huei, Y1 - 2011/07/30/ PY - 2010/12/22/received PY - 2011/07/08/revised PY - 2011/07/09/accepted PY - 2011/8/10/entrez PY - 2011/8/10/pubmed PY - 2012/8/2/medline SP - 1239 EP - 47 JF - Neuropharmacology JO - Neuropharmacology VL - 61 IS - 8 N2 - Carisbamate (CRS, RWJ-333369) is a novel antiepileptic drug awaiting approval for use in the treatment of partial and generalized seizures. Our aim was to determine whether CRS modulates synaptic transmission in the dentate gyrus (DG) and the underlying mechanism. The whole-cell patch-clamp method was used to record AMPA receptor- and NMDA receptor-mediated excitatory postsynaptic currents (EPSC(AMPA) and EPSC(NMDA)) and GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) in granule cells of the DG in brain slices prepared from 3- to 5-week-old male Wistar rats. CRS (30-300 μM) inhibited the evoked EPSC(AMPA) and EPSC(NMDA) by the same extent (20%) with significantly altered CV(-2), suggesting presynaptic modulation. It did not significantly change the inward currents induced by AMPA application. The inhibitory effect of CRS on the evoked EPSC(AMPA) was not occluded by selective voltage-gated Ca(2+) channel blockers, ruling out the involvement of presynaptic Ca(2+) channels. The frequency, but not the amplitude, of spontaneous EPSC(AMPA) was significantly reduced by CRS. However, CRS did not alter either the frequency or the amplitude of TTX-insensitive miniature EPSC(AMPA), indicating an action potential-dependent mechanism was involved. In addition, CRS (100 or 300 μM) did not significantly change the amplitude of the evoked IPSCs. To summarize, our results suggest that CRS reduces glutamatergic transmission by an action potential-dependent presynaptic mechanism and consequently inhibits excitatory synaptic strength in the DG without affecting GABAergic transmission. This effect may contribute to the antiepileptic action observed clinically at therapeutic concentrations of CRS. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/21824485/Carisbamate__RWJ_333369__inhibits_glutamate_transmission_in_the_granule_cell_of_the_dentate_gyrus_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(11)00298-X DB - PRIME DP - Unbound Medicine ER -